The Value of Detecting and Monitoring ctDNA in Uveal Melanoma: Results of a Pilot Study and a Systematic Review

This article presents the results of a prospective pilot study on circulating tumor DNA (ctDNA) monitoring in uveal melanoma (UM) patients, along with a systematic review of the literature to support and contextualize the findings. We investigated the clinical utility of ctDNA variant allele frequency (VAF) for early detection of tumor progression.

We performed serial ctDNA testing using the Ion AmpliSeq Cancer Hotspot Panel v2 and Ion Proton™ sequencing in 3 UM patients (two recurrent, one nonrecurrent) at four time points over 2 years. A systematic review of studies up to June 2024 was also conducted, identifying 32 additional UM patients. In recurrent patients, co-occurring mutations in GNAQ, GNAS, and IDH1 were identified at the time of recurrence, with minimum VAFs of 0.51%, 0.25%, and 0.1%, respectively. In the nonrecurrent patient, pathogenic variants were absent, and VAFs of key genes declined over time. The systematic review supported the association of ctDNA alterations with recurrence and metastasis, identifying critical genes including GNAQ/11, GNAS, IDH1, STK11, FGFR2, and EGFR, many of which interact with the BAP1 signaling pathway.

Serial ctDNA analysis may serve as a noninvasive tool for early detection of recurrence in UM. Co-occurrence of GNAQ, GNAS, and IDH1 mutations may represent a molecular signature of recurrence. Further validation in larger cohorts is needed to define optimal gene panels and VAF thresholds for clinical use.